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  • Kaislasuo, Janina (Helsingin yliopisto, 2015)
    The proportion of nulligravid and nulliparous women is increasing as women delay childbirth in developed countries. Simultaneously, contraceptive failure, unintended pregnancies and abortions, especially in women below the common childbearing age, are a global problem. By promoting intrauterine devices (IUDs) and subdermal implants, referred to as long-acting reversible contraceptives (LARCs), among these women, contraceptive failure caused by non-compliance of the user can be minimized, in addition to providing easy and efficient long-term contraception. However, the risk of difficulties at IUD insertion in nulligravid/nulliparous women, as well as small uterine size, have both been considered as barriers limiting the use of intrauterine contraception (IUC) in these women. The present studies were designed to study the barriers to IUC in nulligravid and nulliparous women. To compare both types of IUC available, we used the levonorgestrel-releasing intrauterine system (LNG-IUS) and the copper-releasing NovaT (TCu380Ag), with identical frames measuring 32 x 32 mm. To exclude any effect of prior pregnancy on the uterine cavity or the cervix, only nulligravid women were included. Difficulties at insertion, menstrual diaries kept after insertion (months 1 3) and at the end of the study (months 10 12) as well as adverse events were compared against uterine cavity measurements and pre-insertion menstrual characteristics reported by the women. In addition, as uterine perforation is mainly seen as a complication related to insertion, we retrospectively analysed women treated for this rare complication between 1996 and 2009 in our hospital district area. We gave 165 nulligravid women requesting their first IUD a free choice between the two IUDs after contraceptive counselling. The majority, 113 women (68.5%), chose the LNG-IUS and 52 women (31.5%) chose the copper IUD. Insertion was easy in 89% of the women. The women were satisfied, with only 17/135 women (12.6%) available for follow-up discontinuing because of adverse events. The reported numbers of days of bleeding and pain were similar to that in earlier reports on parous women. Severe pain at insertion was reported by 56.5% of the women and severe dysmenorrhoea the only factor predicting severe pain (OR 7.9, 95% CI 2.5 24.9, p less than 0.001). Dysmenorrhoea was also related to more pain during the first months with both devices. Baseline spontaneous bleeding predicted bleeding with the LNG-IUS, but not with the copper IUD. Among women using the LNG-IUS, scanty menstrual bleeding (OR 8.2, 95% CI 1.4 48.2, p=0.02) and smoking (OR 8.2, 95% CI 1.8 38.6, p=0.007) predicted amenorrhoea at one year. Uterine measurements, particularly fundal cavity width, were small in comparison to the devices in a majority of the women. The odds of a difficult or failed insertion increased with shorter uterine length and a steeper flexion angle, but the great majority of insertions, even in small and more flexed uteri, were uneventful. Cervical tightness was the main reason for problems in cases of difficult insertion. No uterine threshold measurements predicting difficulties were found. Small uterine measurements were associated with both less bleeding and less pain among LNG-IUS users. Women with the widest fundal widths reported significantly more pain at the end of the one-year follow-up period compared with those with smaller widths. Uterine size did not affect bleeding in connection with the copper IUD, but there was a slight tendency towards more pain during long-term use among women with smaller uterine cavity measurements, although size groups were small with this device. Uterine size did not predict adverse events. We found 75 cases of surgically treated uterine perforation during the 15 year long study period. The incidence of perforation was low, 0.4/1000 insertions, and similar with both types of IUC. Postpartum insertion, earlier presented as the main risk factor of uterine perforation, was also common in this population (64%). The majority of cases, 71%, presented with complaints of abnormal bleeding or pain, but 29% were asymptomatic and diagnosed in connection with missing threads or pregnancy. Pregnancy was more common with a misplaced copper IUD, 33% vs. 7% with a misplaced LNG-IUS (p=0.009). We found no severe complications or intra-abdominal adhesions caused by the misplaced devices. Adhesions were local and more common in copper IUD users (58% vs. 20%, p=0.002). In conclusion, nulligravid women are satisfied users of modern IUC, with continuation rates and bleeding and pain profiles similar to those in parous women. Small uterine cavity measurements are not a barrier to IUC and pre-insertion ultrasonographic evaluation of uterine cavity size is unnecessary. As dysmenorrhoea predicts both severe insertion pain and pain during the first months of IUD use, analgesia and counselling for these women should be highlighted. Although rare, the risk of uterine perforation is increased during the postpartum period, probably reflecting uterine involution as the main reason for this complication. Neither symptoms nor surgical findings are severe in connection with current devices.
  • Metsola, Lalli (Helsingin yliopisto, 2015)
    This is a study of Namibian ex-combatant and veteran policies after the country s transition to independence in 1990. Instead of assessing the successfulness of reintegration against its stated objectives or the perspective of post-conflict policy discourses, it examines the politics of reintegration as a process of multiform negotiation over recognition and entitlements for the ex-combatants, and political authority and legitimacy for party and government leaders. The study interrogates the ways in which this process reflects and contributes to postcolonial Namibian politics, state formation and citizenship. It is based on nine months of fieldwork in 2002, 2003 and 2009 and its main sources include ethnographic observation, life historical interviews with ex-combatants, thematic interviews with politicians and civil servants, grey literature as well as Namibian newspapers and internet sources. The study finds that instead of being a neutral exercise in post-conflict management and peacebuilding, Namibian reintegration has been motivated by more exclusive ideas of the nation and by the special bond between the ruling party and the former liberation movement Swapo and its formerly exiled cadres. This close tie and the characterization of Swapo combatants as heroes who hold a special place in the Namibian narrative of national liberation have repeatedly enabled Swapo ex-combatants to demand recognition, employment, monetary compensation and other benefits. Coupled with this, the relative strength of the Namibian state and economy has made it possible to plan and implement ex-combatant reintegration as a predominantly domestic process without the close involvement of international agencies. Hence, it has been possible to diverge from mainstream disarmament, demobilization and reintegration (DDR) programmes and attempt to solve the ex-combatant question by broad-based public employment. After most ex-combatants were employed in the late 1990s and early 2000s, however, their demands and policy responses shifted towards monetary compensation. The domestic character of Namibian reintegration also made it possible to implement ex-combatant and veteran policies selectively so that former Swapo exiles have gradually been transformed into an officially recognized group of veterans while their former enemies, Namibian fighters of South African surrogate forces, have been sidelined. This process of domestically driven, selective reintegration has multiple broad implications. First, as Namibia has recently emerged from a long period of violent conflict, security concerns and the imperative to control organized violence are clearly visible. The targeting of Swapo ex-combatants in reintegration and their recruitment to the public service, particularly the uniformed services, have relinked their fates with that of the Swapo government, pacifying them and making them useful in consolidating the hold of the regime over the security agencies and the marginal and frontier areas and populations. Indeed, a key reason why the demand politics of the ex-combatants have been so successful is that their interests have been largely congruent with the perceived interests of the political elite. Second, the tendency of Namibian reintegration to entrench involvement in liberationist history as a criterion of full membership in the political community, creating an ever-widening circle of veterans versus others, provides and interesting comparison with struggles over recognition and citizenship elsewhere in Africa which are often framed in terms of language, religion, ethnicity, race or historical origins. The movements thus generated may adopt anti-national stances but they are as likely to seek to reformulate and colonize nationalism itself. Namibian ex-combatant reintegration, on the other hand, exemplifies a situation where nationalism as a supposedly unifying force still has salience but has been appropriated by a particular narrative of belonging. Thus, instead of representing a break from inclusive citizenship towards increasingly codified particular identities that compete within the national space, the Namibian case demonstrates the coexistence of a legal concept of universal national citizenship with a pervasive ideology of national belonging. The latter, however, inherently contradicts the supposed universalism of legal citizenship. The long-term effects of Namibian veteran politics remain to be seen. On the one hand, the aim to reconcile and build a nation, evident in some of the decisions and statements associated with reintegration as well as in Namibian political discourse more generally, is countered by the persistence of pre-independence political logics and divisions, and a concentration of power according to liberationist fault lines. It is not surprising that a militant version of nationalism seems appealing to certain political elites in their bid to justify the current regime and entrench their own positions in it. On the other hand, in the long run the politics of ex-combatants and veterans may also offer a template for more broad-based demands that question entrenched patterns of economic and political privilege, and provoke responses that may lead towards more inclusive citizenship and more broadly legitimate authority.
  • Salo, Merja (Helsingin yliopisto, 2015)
    All of the Volga region languages investigated in this study (Mordvin, Mari, and Chuvash) have a rich derivational morphology. In general linguistics terms, they all have a passive classified as a reflexive passive. The relationship between the derivative and the root verb is described using the valence roles of case grammar. The role of the first, or primary, actant is crucial in defining all the different meanings of the derived verbs in question. The main roles used to express the first actants are: AGENTIVE, ACTOR, NEUTRAL, EXPERIENCER, and FORCE. In Mordvin, passive sentences contain a special polyfunctional derivative suffix, -v-, which also renders the automative, reflexive, perfective and unintentional meaning, as well as dynamic modality. Besides the -v-, the rare and almost forgotten -t-, shares most of these meanings. Moreover, in many respects, these suffixes show parallel development. Contemporary speakers use these t-verbs to express unpleasant feelings and negative physiological states. t-derivatives can also be used to describe weather conditions as the only constituent part of a sentence, but this use is marginal. These two usages bring the t-derivatives close to the impersonal in the Indo-European languages. Furthermore, Mari and Chuvash have very similar suffixes, the reflexive-passive -ǝlt- or -Alt-, and the passive -l- and the reflexive -n-, respectively. Their passives do not permit an agent, and automative meanings are common, as are reflexives. My material proves that both Chuvash suffixes can have identical meanings. Interestingly, in all three languages, zero meaning occurs with intransitive root verbs. Finally, meteorological verbs in 14 Uralic languages were studied from a syntactic perspective. Some verbs have zero valence, others display a more or less semantically faded subject, while others feature an object. With causative transitive verbs, the prevailing restriction seems to be that either a subject or an object is possible, but both are not. Earlier, it was assumed that the sentence type V is Uralic, but according to my findings it is absent in some of the Samoyed languages and that the SV or VS type is more widely known. The introduction provides background information on the history of the Volga region and the many alternative ways of expressing passive and related meanings in the Uralic languages. An agent in a passive sentence is rare, and thus special attention is given to its expression. It seems obvious that the agent has been completely absent in passive sentences in the Uralic and Turkic languages. Many of these languages, however, have now developed an agent under the influence of the Indo-European languages. Furthermore, the construction with a dummy subject has started to spread and now occurs in the Saami and Finnic languages.
  • Hirvilammi, Tuuli (Kelan tutkimusosasto, 2015)
    The starting point of this study is a paradoxical situation: the wellbeing of average Finns is very high but simultaneously their environmental impacts threaten the carrying capacity of the earth. The paradox raises the question of what would sustainable wellbeing be and how is it to be studied. This study aims to develop a theory of sustainable wellbeing that recognizes the interaction between people and nature, as well as the goals of sustainability. In this interdisciplinary study the ecological issues are integrated into wellbeing research both in theory and in the empirical research settings. The empirical substudies are based on data that explores the wellbeing, standard of living and natural resource use (material footprints) of minimum income receivers. Material footprints were measured with the MIPS method.The results present a theory of sustainable wellbeing that is based on a relational conception of man. It enables us to see the connections between people and ecosystems, and humans as a part of nature. Sustainable wellbeing is defined as an entity that consists of a sufficient and sustainable standard of living, purposeful and responsible behavior, significant relations and an alert presence. The study develops a dynamic framework that can be used to explain the relations between capabilities, functionings and natural resource use. In order to be sustainable, wellbeing should be eco-efficient, which means satisfying needs with a minimal load on the environment. The results also present an interdisciplinary methodological setting, which can be used to assess the limits of a socially and ecologically sustainable standard of living. The aim of the sustainable standard of living is to secure all people with necessary resources within the carrying capacity of nature.
  • Tohmola, Niina (Helsingin yliopisto, 2015)
    Metabolites are low molecular weight compounds participating in different functions of cellular systems. Metabolites can be used as diagnostic biomarkers for numerous diseases. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a powerful tool in quantification of metabolites from various sample matrices. Good sensitivity and specificity are the main benefits of the technique. Mass spectrometry is commonly used in industry, drug research and clinical diagnostics. Extensive validation of newly developed analytical methods will construct the basis to a reliable assay, and it is significant especially when analysing e.g. patient samples. The aim of this study was to develop quantitative assays for metabolites from biological samples for biomedical research and clinical diagnostics. We designed and constructed an on-line high performance liquid chromatography (HPLC) equipment and validated an assay for direct quantification of extracellular metabolites from cell cultivation. Automated sampling for LC-MS/MS analysis of intracellular metabolites was connected to the on-line system. The on-line analysis improves the methodology and shortens the time of analysis. Furthermore, a frequent sampling data can provide valuable information about physiological indications in various cell cultivations. On-line HPLC is suitable for various biotechnological applications because of its ability to monitor and collect data during cell cultivation. We developed and validated LC-MS/MS assays for neuroendocrine tumor (NET) biomarkers 5-hydroxyindole acetic acid (5-HIAA) and vanillylmandelic acid (VMA) from human serum. Generally, urinary HPLC assays are used for the determination of NET markers. HPLC assays have certain limitations and 24-h urine collection is laborious. Our LC-MS/MS assays are specific, fast and well suited for diagnostics of NETs. Furthermore, guidelines for urine collection advise to refrain from serotonin-containing foods for three days before sample collection. We showed that such a diet restriction before serum 5-HIAA assay is not necessary. Instead, one day serotonin-free diet before sampling is sufficient because the half-life of 5-HIAA in circulation was found to be 1.3 hours. All assays developed during this study were sensitive and had a wide linear range. Our serum 5-HIAA LC-MS/MS assay is routinely used for the analysis of NET patient samples at the Helsinki University Central Hospital Laboratory, HUSLAB. Serum VMA LC-MS/MS assay will be in routine use in the HUSLAB in near future. Furthermore, On-line HPLC Ltd, (Helsinki, Finland) has commercialized the on-line HPLC equipment developed in this study.
  • Kankainen, Matti (Helsingin yliopisto, 2015)
    Lactobacilli are generally harmless gram-positive lactic acid bacteria and well known for their broad spectrum of beneficial effects on human health and usage in food production. However, relatively little is known at the molecular level about the relationships between lactobacilli and humans and about their food processing abilities. The aim of this thesis was to establish bioinformatics approaches for classifying proteins involved in the health effects and food production abilities of lactobacilli and to elucidate the functional potential of two biomedically important Lactobacillus species using whole-genome sequencing. To facilitate the genome-based analysis of lactobacilli, two new bioinformatics approaches were developed for the systematic analysis of protein function. The first approach, called LOCP, fulfilled the need for accurate genome-wide annotation of putative pilus operons in gram-positive bacteria, whereas the second approach, BLANNOTATOR, represented an improved homology-based solution for general function annotation of bacterial proteins. Importantly, both approaches showed superior accuracy in evaluation tests and proved to be useful in finding information ignored by other homology-search methods, illustrating their added value to the current repertoire of function classification systems. Their application also led to the discovery of several putative pilus operons and new potential effector molecules in lactobacilli, including many of the key findings of this thesis work. Lactobacillus rhamnosus GG is one of the clinically best-studied Lactobacillus strains and has a long history of safe use in the food industry. The whole-genome sequencing of the strain GG and a closely related dairy strain L. rhamnosus LC705 revealed two almost identical genomes, despite the physiological differences between the strains. Nevertheless of the extensive genomic similarity, present only in GG was a genomic region containing genes for three pilin subunits and a pilin-dedicated sortase. The presence of these pili on the cell surface of L. rhamnosus GG was also confirmed, and one of the GG-specific pilins was demonstrated to be central for the mucus interaction of strain GG. These discoveries established the presence of gram-positive pilus structures also in non-pathogenic bacteria and provided a long-awaited explanation for the highly efficient adhesion of the strain GG to the intestinal mucosa. The other Lactobacillus species investigated in this thesis was Lactobacillus crispatus. To gain insights into its physiology and to identify components by which this important constituent of the healthy human vagina may promote urogenital health, the genome of a representative L. crispatus strain was sequenced and compared to those of nine others. These analyses provided an accurate account of features associated with vaginal health and revealed a set of 1,224 gene families that were universally conserved across all the ten strains, and, most likely, also across the entire L. crispatus species. Importantly, this set of genes was shown to contain adhesion genes involved in the displacement of the bacterial vaginosis-associated Gardnerella vaginalis from vaginal cells and provided a molecular explanation for the inverse association between L. crispatus and G. vaginalis colonisation in the vagina. Taken together, the present study demonstrates the power of whole-genome sequencing and computer-assisted genome annotation in identifying genes that are involved in host-interactions and have industrial value. The discovery of gram-positive pili in L. rhamnosus GG and the mechanism by which L. crispatus excludes G. vaginalis from vaginal cells are both major steps forward in understanding the interaction between lactobacilli and host. We envisage that these findings together with the developed bioinformatics methods will aid the improvement of probiotic products and human health in the future.
  • Soppela, Ira (Helsingin yliopisto, 2015)
    The manufacturing of the most common pharmaceutical dosage forms, tablets, requires good mass flowability and uniform particle size distribution. Granulation is often needed to improve these properties prior to tablet compression. Thus, rapid methods for analysing the key powder and granule properties, such as particle size, flowability and moisture content are needed. Until recently, the development and control of pharmaceutical unit operations was based on an empirical approach rather than process understanding. To be able to build quality into the products, improved understanding of materials and processing is needed. This can be reached by developing complementary automated analytical methods that are suitable for continuous on-line or in-line process monitoring. The aim of this thesis was to investigate whether modern analytical tools can provide rapid and reliable real-time insight into powder performance during solid dosage form processing. The first study evaluated the impact of paracetamol loading and the physical characteristics of powders on the flowability of microcrystalline cellulose and paracetamol mixtures. A novel small-scale flow device proved to be suitable for rapid flowability screening of different formulations. Particle size distribution and drug loading had the largest impact on the flowability. The main focus of this thesis was on the utilisation of image analysis, near infrared (NIR) spectrocopy and process measurements as complementary process analytical tools during granulation. In addition to particle size distribution, the images revealed batch specific granule growth and attrition behaviour in real time. The changes in granule size were clearly linked to the continuously measured process conditions. Moreover, changes in image brightness during drying reflected the removal of water from the granules. The continuous moisture measurements based on process air moisture content and NIR spectroscopy provided real time information on the moisture content as well as the batch moisture profile during processing. The comparison of the methods also enabled the evaluation of the location of water in the process. The combination of on-line photometric imaging and near-infrared spectroscopy with continuous in-line process measurements facilitated continuous evaluation of key product properties during fluid bed granulation and provided insight into batch performance. The powder characterisation and process analytical technology (PAT) tools applied in this work enabled rapid and non-destructive determination of key powder and granule quality attributes. Even small changes in the material properties during processing were detected using the continuous and complementary process analytical measurements.
  • Santala, Johanna (Helsingin yliopisto, 2015)
    The spraing symptoms on potato tubers caused by Potato mop-top virus (PMTV) are considered as one of the most important quality problems in potato production in the Nordic countries. PMTV has a tripartite single stranded positive sense RNA genome. RNA-RdRp encodes the viral replicase. PMTV-CP codes for a coat protein (CP) and a read through part of CP associated with the vector transmission. RNA-TGB encodes three movement related triple gene block proteins (TGBp) and an 8 kDa cysteine rich protein (8K) implicated as suppressor of RNA silencing. The aim of this study was to find new host and viral factors affecting PMTV infection and detection. As only few PMTV sequences were available in databanks prior to this study, 28 PMTV isolates obtained from symptomatic and asymptomatic potato tubers were partially sequenced. Two distinguishable types of RNA-CP and RNA-TGB were found, each showing only little genetic variability. Occurrence of tuber symptoms did not correlate with the types of PMTV RNA but seemed to depend on potato cultivar and environmental conditions. Indeed, in some cultivars almost all PMTV infections were asymptomatic. Potato sprouts grown in dark were found to contain high titers of PMTV and can be used to test potatoes for PMTV. However, viral titers decreased rapidly in sprouts exposed to light. Accumulation of PMTV specific small interfering RNAs (siRNA) in both dark grown and light exposed sprouts indicated that RNA silencing was acting against the virus in the sprouts. Moreover, the amount of viral siRNA, as opposed to viral RNA, did not decrease in the light-exposed sprouts indicating that RNA silencing was enhanced in the light exposed sprouts. PMTV TGBp1 was found, and PMTV 8K confirmed, to act as weak suppressor of silencing. PMTV TGBp3 interacts with TGBp2 to target viral ribonucleoprotein complexes to plasmodesmata and further to adjacent cells, but TGBp2 and TGBp3 are recycled through endocytosis. PMTV TGBp3 was found to be phosphorylated on two tyrosine residues, both of which are located within tyrosine based sorting motifs implicated in endocytosis. Mutation of one of the sites led to strengthening of the TGBp2-TGBp3 interaction and restricted the virus to the originally infected cell. Therefore, tyrosine phosphorylation of TGBp3 seemed to affect PMTV infection by regulating the interaction between TGBp2 and TGBp3. According to this study, the current reliance on symptoms in seed potato inspections for PMTV is unreliable and risks spreading the virus to new fields. Light was found to accelerate antiviral silencing in sprouts, which may explain why PMTV and its symptoms are rarely detected in aboveground parts of potato plants. Tyrosine phosphorylation of TGBp3 marked the first evidence that viral proteins can be tyrosine-phosphorylated in plants. This find could offer means for breeding PMTV resistant potato cultivars.  
  • Nikkonen, Taru (Helsingin yliopisto, 2015)
    In photosynthetic systems, chlorophylls have a vital role in converting the energy of light into chemical energy. The absorption by antenna pigments and subsequent excitation energy transfer to the reaction centre, where charge separation processes take place, result in an electrochemical potential which is utilized in carbohydrate production. The structural properties of the chlorophylls as well as supramolecular interactions, mutual distances and orientations in their natural environment, determine the function of each pigment. The aim of this doctoral thesis was to mimic photosynthetic systems and to develop chlorophyll-based structures and materials for artificial photosynthetic applications. The literature review of this thesis will concentrate on the structural, photophysical, and supramolecular properties of chlorophyll derivatives. Their functions in natural environments and their potential use in artificial light-harvesting assemblies will be thoroughly discussed. The focus of the literature review will be solely on biomimetic systems that are built by the supramolecular approach. In addition to chlorophyll (chlorin) assemblies, supramolecular systems of some important chlorophyll analogues (e.g., porphyrins) are presented. The experimental part of this thesis is based on publications I-IV. Chlorophylls were separated from green algae and modified synthetically to achieve the desired photophysical and structural/supramolecular properties. In the first part of this thesis, the energy transferring antenna structure was designed utilizing a polymer, poly(4-vinylpyridine) (P4VP), to which Zn chlorin pigments were bound noncovalently through metal-ligand axial coordination. The investigation of the assemblies revealed tight coordination both in solution and solid state films. The absorptive and emitting regimes of the solid state Zn chlorin-P4VP assemblies with variable doping levels were determined. In another part of this thesis, a series of covalently linked chlorin dimers were synthesized and their intramolecular folding abilities were investigated using both spectroscopic and theoretical techniques. It was proven that chlorin dimers fold into a C2-symmetric structure via hydrogen bonding when the linker has a suitable length. To be exact, the folding was shown to be favored with 4-10 carbon atom linkers, of which the carbon linker with a 6-atom backbone was the most optimal. As a continuation of the work, the electron donating chlorin dimer was attached to an electron acceptor, fullerene, to give a chlorin dimer−azafulleroid. The experimental spectroscopical studies and theoretical investigations showed that the chlorin dimer−azafulleroid undergoes conformational switching depending on the polarity of the media. In nonpolar media, the hydrogen bonded folded dimer is present, while in polar media the two hydrophopic chlorins wrap around the azafulleroid. The photophysical studies indicated that the lifetime of photoinduced charge separation is longer in the folded conformation having similarities to the natural photosynthetic reaction centre special pair, that is, the self-assembled chlorophyll dimer that performs the primary electron transfer step in photosynthesis. Strong electron donors, such as ferrocene, Fe(η5-C5H5)2, and ruthenocene, Ru(η5-C5H5)2, are often utilized as electron donors in donor-acceptor pairs or conjugated to electron donors to achieve improved charge transfer properties with electron donating moieties. For the first time, metallocene-appended (either [Fe(η5-C5H5)(η5-C5H4)] or [Ru(η5-C5Me5)(η5-C5H4)]) chlorin derivatives were synthesized. The resulting metallocene-chlorins oxidized spontaneously under air to give certain oxidation products depending on the type of metallocene attached to the aromatic chlorin macrocycle. The oxidized metallocene-chlorins were characterized by steady-state and time-resolved absorption and emission spectroscopy.
  • Parviainen, Suvi (Helsingin yliopisto, 2015)
    It has been estimated that up to half of people living in industrial societies will get cancer. Almost all cancer deaths are caused by metastatic disease and only few metastatic solid tumors can be cured with available therapies. Therefore, novel therapeutic modalities are needed. Genetically engineered oncolytic viruses such as adenoviruses and vaccinia viruses are a promising therapeutic approach given their capacity to specifically replicate in and kill tumor cells as well as to reach distant metastasis. Oncolytic viruses have demonstrated good safety, tolerability and promising signs of anti-tumor efficacy in several clinical trials, but the efficacy of the therapy needs improvement to reach its full clinical potential. Adenoviruses are one of the most studied vectors in oncolytic virotherapy. Two major obstacles limiting the efficacy have been insufficient transduction of the tumor cells and the recognition of the virus by the immune system, which rapidly clears the virus from systemic circulation, hampering the overall efficacy. This study shows that novel capsid modifications can increase the transduction efficacy and oncolytic potency of the virus, and that embedding oncolytic virus in a silica implant might help to circumvent the problem of clearance by prompting only modest immune responses against the virus. Recently, arming oncolytic viruses with immunomodulatory molecules has been a major focus in virotherapy. Immunotherapy means inducing the patient´s immune system to recognize and attack the tumor and has been recently linked with oncolytic virotherapy, as the replication of the virus in the tumor can be immunogenic per se and also release cancer epitopes available for antigen-presenting cells. Host immune responses have been shown to be a key player in oncolytic virotherapy as the balance between anti-viral and anti-tumoral immunity determines the efficacy of the therapy. Oncolytic vaccinia virus possesses unique immunogenicity and mechanisms of action that are distinct from other treatment modalities, and its self-perpetuating nature provides an ideal platform for therapeutic transgenic insertion. Therefore we engineered novel oncolytic vaccinia viruses with granulocyte-macrophage colony-stimulating factor (GMCSF) or CD40-ligand and studied their ability to increase the therapeutical outcome and anti-tumor immune responses in preclinical animal models. In the final part of the thesis the life cycle of oncolytic vaccinia virus was studied in more detail as we were able to show that the life cycle was compromised in a feline squamous cell carcinoma cell line. This finding might be important for a deeper understanding of the vaccinia virus-host cell interactions.
  • Törnroos, Maria (Helsingin yliopisto, 2015)
    The role of individual differences in perceptions of stress has long been recognized. Despite this, the models that are used to measure stress at the workplace the job strain model and the effort-reward imbalance model were developed to assess strenuous work characteristics and their health effects, regardless of the individual. Because work characteristics are usually measured using self-reports the measures cannot be completely objective. The present study examined the susceptibility of the job strain model and the effort-reward imbalance model to Five-Factor personality traits and cynicism. In addition, this study tested the longitudinal measurement invariance of the effort-reward imbalance scales. This study was part of the ongoing prospective, population-based Young Finns study. The measurements for the present study were carried out in 2001, 2007, and 2012. Five-Factor personality traits were assessed with a questionnaire on the Five-Factor model, and cynicism was assessed with a scale derived from the Minnesota Multiphasic Personality Inventory. Work characteristics were measured with questionnaires on the job strain model and the effort-reward imbalance model. The results showed that high neuroticism was associated with higher job strain and higher effort-reward imbalance and that high agreeableness was associated with lower job strain and lower effort-reward imbalance. High extraversion, high openness, and high conscientiousness were associated with lower job strain. Furthermore, high conscientiousness was related to lower effort-reward imbalance only in men. High job strain prospectively predicted higher cynicism six years later. The effort-reward imbalance scales achieved strict longitudinal measurement invariance and showed adequate criterion validity. Although developed to measure the structural work environment, the job strain model and the effort-reward imbalance model seem to be susceptible to Five-Factor personality traits especially to neuroticism and agreeableness. In addition, high job strain seems to have far reaching consequences on cynical attitudes. Furthermore, the results show that scores on effort-reward imbalance from different time points can reliably be compared with each other. This study shows that organizations and occupational health services should apply a more person-oriented approach to increasing wellbeing at work.
  • Rantanen, Ville (Helsingin yliopisto, 2015)
    Images provide invaluable information to Biomedicine. Especially, microscopy as an information source has been providing knowledge for research and clinical diagnostics. We have moved away from simply looking at the images to quantifiable computerized image analysis. Over the last decades, image analysis developers have prepared algorithms and software to address various scientific enquiries using images. These software are often created for a single purpose. Naturally, not even the most generic software can include all the algorithms ever created. From an image analysis developer point of view, the choice of software creates limitations. It limits the developer to the algorithms included and to the language it was developed in. Even if the software is modular and extendable, a specific language is required and the earlier algorithm implementations would have to be ported. This thesis presents an integration platform for image analysis: Anima. It is capable of using existing software and including them in analysis workflows. Since image analysis is very case specific, custom processing commands are frequently needed. Anima comes with a large number of data and image analysis components developed directly for the platform, as well as components that send custom commands to the integrated software. All of the components can be executed in a single analysis pipeline. Anima itself is built on top of Anduril, another software, inheriting its software architecture. Anduril gives Anima the power of parallel processing and rerun prevention mechanism, speeding up the development cycle of new algorithms. The usability of Anima for method development is shown by implementing new segmentation algorithms and visualization tools. The tools and methods are all suited to large data sets. To display the modularity, the tools are published as separate programs that are then integrated in Anima. The usefulness of the platform is shown by applying it in different biomedical research settings. The settings include different organisms: human, rat and nematode; different sample material: brain tissue, lymphatic nodes and serum; and different medical interests: cerebral ischemia, cancer and allergy. Anima is a versatile open-source image analysis platform, that encourages the use of best practices of programming habits. It makes the development of analysis workflows and individual algorithms more efficient.
  • Rantala, Mari H. (Helsingin yliopisto, 2015)
    Fertility in dairy cows has decreased worldwide, also in Finland. The most common reason for treatments of dairy cattle is various fertility disorders (18 % of all animals in 2013). In practice, decreased fertility warrants use of hormonal estrus synchronization protocols to control follicular waves and luteal regression to achieve acceptable pregnancy rates, without unwanted side effects such as short estrous cycles. In the earlier studies of our research group, short estrous cycles were noted in some cyclic dairy heifers and cows when estrus and ovulation were induced with agonistic analogues of prostaglandin F2α (PGF2α) and GnRH treatments administered 24 h apart. Possible causes for such induced short estrous cycles were further elucidated in the four experiments described in this thesis. Estrus and ovulation were induced with PGF2α and GnRH given 24 h apart during early (Day 7 after ovulation) or late (Day 14 after ovulation) diestrus. Also the effect of gonadorelin doses of 0.1 mg or 0.5 mg given 24 h after PGF2α on the occurrence of short estrous cycles, and on the preovulatory release of LH during 6 h following the gonadorelin administration was investigated. The effect of the time interval between PGF2α and GnRH (0 vs. 24 h) given during early diestrus on the occurrence of short estrous cycles was investigated in cyclic dairy heifers and cows. The expression of endometrial receptors of oxytocin, estrogen-α and progesterone as well as enzymes 20α-hydroxysteroid-dehydrogenase and cyclo-oxygenase-II, on Days 2 and 5 after ovulation was analyzed with real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. The occurrence of induced short estrous cycles was significantly increased with simultaneous administration of PG and GnRH, but was neither related to the size of the preovulatory follicle nor to the GnRH-induced preovulatory release of LH. Also the basal postovulatory release of LH on Days 1, 3 and 5 after ovulation was similar for induced short and normal length estrous cycles. Lower basal LH concentration after ovulation coincided with higher progesterone concentration. The size of the preovulatory follicle was significantly larger when PG and GnRH were given 24 h apart during early diestrus in comparison with late diestrus, but the occurrence of short estrous cycles was similar. The size of the preovulatory follicle in cows did not correlate with the preovulatory secretion of estradiol-17β. The endometrial expressions of receptors and enzymes analyzed were similar for short and normal length estrous cycles. The results described should be taken into account in estrus synchronization protocols utilizing sequential treatments with PG and GnRH.
  • Ojajärvi, Anni (Nuorisotutkimusverkosto/Nuorisotutkimusseura, 2015)
    This study observes young men´s health behaviour during military service. In addition to individual health choices, the study analyses how the practices of the military institution, the conscript community and the images of and expectations for the conscript role guide and restrict the health choices of the conscripts. The purpose of this study is to determine how health behaviour is constructed in different social contexts, amongst the orders of a total institution. The study is situated in the field of qualitative health research. The research material involves an ethnographic field study conducted in Parolannummi Panzer Brigade in 2008. The researcher participated, during eight weeks and full time, in the initial conscript training, lived with the conscripts and observed the everyday life in the army. The conscripts were also interviewed; altogether 39 individual interviews of 15 men and 8 women, some of them twice, were made. On the basis of the results, the conscripts´ health behaviour can be determined as a communal process that is restricted by the institution. An individual conscript makes choices in the midst of the strictly defined everyday life of a total institution and the social reality of the conscript community. In the absence of a strong personal motive for guiding the individual health choices, the young person adheres to institutional practices and to the conscript community. The logic and objectives of military training or the practices of the conscript community do not always support the aims of health education. Instead, the everyday life in the army often contradicts the health perspective. In the empirically chapters the study analyses the limits between sickness and health, eating, smoking and alcohol consumption. Findings include answers to questions such as how smoking may seem as a smart choice from the conscript point of view, how collective army stories are related to conscripts´ alcohol consumption, how being occasionally sick is connected to conscript´s social identity, and how eating is split to fuelling up and eating for pleasure. At the same time, the study discovers how a 21st century young man revives the ethos of sustaining but, differing from the traditional ethos of self-sustaining, shares his difficult life situations with others. The empirical chapter also introduces conscript ideals, constructed on the basis of the study material, which define the limits of a socially acceptable conscript role. Whenever aiming at influencing the conscripts´ health behaviour, the study calls attention to everyday practices in the institution and the conscript community´s ways of acting.
  • Virtanen, Anni (Helsingin yliopisto, 2015)
    High coverage amongst those at risk and a high attendance rate are essential in achieving a good impact in a cervical cancer screening programme. In Finland, attendance in the programme is approximately 70% with a slight decreasing trend. There is wide variation in the current invitation practice between municipalities. The introduction of human papillomavirus (HPV) testing in cervical cancer screening has brought about a new possible means of improving attendance rates, as HPV-testing can be performed on self-collected samples. This offers the opportunity to supply sampling devices directly to the homes of the women (self-sampling). The aim of this study was to investigate the effects and feasibility of using self-taken samples for HPV-testing to conduct cervical cancer screening of non-attendees to the Finnish cervical screening programme. The effect on attendance to the screening programme, on overall screening test coverage (including also testing outside the screening programme), on the yield of precancerous lesions detected by screening and on the costs of a screening programme were assessed, as were women s views on this new screening modality. The effects of self-sampling were first studied as a first reminder (i.e. among non-attendees after the primary invitation) in a randomized setting in comparison to a reminder letter, and then in a non-randomized setting as a second reminder after two invitation letters. As a first reminder to non-attendees after the primary invitation, a self-sampling test resulted in somewhat higher attendance than a reminder letter. The difference was small, and in terms of resulting costs (price per extra screened woman and price per detected CIN2+ lesion), a reminder letter with a pre-assigned appointment time is a more feasible choice than a self-sampling test. However, self-sampling can be used to increase screening attendance as a second reminder after two invitation letters. Overall attendance rates increased by 4-8%, and the combined effect of reminder letters and self-sampling showed a 12-23% increase. The yield of detected CIN2+ lesions increased by 25-33% with two reminders. As opportunistic screening is very common in Finland, the increase in overall test coverage remained smaller than the increase in the uptake to the programme. Based on a questionnaire study conducted alongside self-sampling, self-sampling at home helps to overcome both practical and emotional barriers to traditional screening. Women who took part in screening by self-sampling reported mainly positive experiences, but negative experiences were more common among women with a mother tongue other than Finnish or Swedish. The invitation protocol preceding the self-sampling option must be carefully arranged to achieve optimal attendance. A total attendance of well over 80% is achievable in the national programme if personal invitations and reminder letters to non-attendees are sent, scheduled appointments are used in both letters and self-sampling tests are sent to those women who still do not attend.
  • Häkkinen, Margareeta (Helsingin yliopisto, 2015)
    Opioids are the most important drugs causing fatal poisonings. Determining whether an opioid death was poisoning may, however, be difficult even if involving appropriate toxicological laboratory investigation. Apart from heroin, little statistically significant data-analysis is available for interpretation of blood concentrations of opioids from various types of post-mortem cases. Tolerance, route of administration, and delay of death after drug administration all influence postmortem drug concentrations. In this thesis, quantitative blood concentration data extracted from the high-quality Finnish postmortem toxicology database was the investigative tool to overcome this problem. Opioid deaths typically involve drug abuse, and suspected drug-abuser deaths must, by Finnish law, undergo medico-legal examination. Medico-legal autopsy in these cases includes comprehensive drug screening and, based on its results, more specific drug quantification. This thesis combined concentration data stored in the postmortem toxicology database with information from death certificates issued by forensic pathologists to allow statistical comparisons between drug poisonings and other deaths, as well as between drug abusers and other users. Concentration data mainly involved drug concentrations in postmortem femoral blood, but drug concentrations in urine and parent drug/metabolite concentration ratios also allowed assessment of buprenorphine, codeine, and tramadol deaths. Opioid poisonings proved to be mainly unintentional polydrug poisonings, regularly involving benzodiazepines, gabapentinoids, and other psycholeptics. Buprenorphine and methadone blood concentrations in fatal poisonings remained within their therapeutic ranges, and these two opioids involved mostly abuse. Concentrations of the weak opioids tramadol and codeine were above their therapeutic ranges both in abuser cases and in fatal poisonings. Tramadol abuse was common but abuse of oxycodone, fentanyl, and codeine was rather low compared to their therapeutic use. Abuse of the gabapentinoids pregabalin and gabapentin was strongly associated with opioid abuse, and compared to gabapentin abuse, pregabalin abuse was proportionally more frequent. To prevent parenteral buprenorphine abuse, opioid maintenance treatment applied a combination product of buprenorphine-naloxone. This combination product is, however, abused as well, and monitoring its abuse is challenging. In this study, urine samples collected from living patients at different phases of opioid maintenance treatment supplemented the postmortem data. Based on the criteria established with these patients, combined with postmortem data and proper background information, a urine concentration limit was estimated for suspected parenteral abuse of the buprenorphine-naloxone product in postmortem cases. Deaths and fatal poisonings due to parenteral buprenorphine-naloxone abuse occurred frequently, and abuse of the combination product was proportionally even more fatal than was abuse of buprenorphine. The results of this study will assist in medico-legal cause-of-death investigations through providing quantitative reference concentrations for the interpretation of opioid-related deaths. Further, estimating the proportion attributable to prescription opioid abuse compared to that of other opioid use and creating abuser profiles for various opioids can promote public health through proper drug policy. In a clinical context, results may be helpful in evaluating possible drug abuse and compliance among prescription-drug users. Detecting abuse of these important yet addictive medications is vital in promoting welfare and drug safety.
  • Miettinen, Samuli (2015)
    How is EU criminal legislative competence regulated after the Lisbon Treaty? The European Union has always had powers which affect national criminal law. Classic internal market judgments consider whether national criminal law measures are justified restrictions of freedom of movement. The Union s direct legislative powers in this field have developed more slowly through international agreements, Treaty revision and the case law of the Court of Justice on implied powers. This study asks what powers have been conferred on the Union in the field of substantive criminal law and how the exercise of its powers may be reviewed after the entry into force of the Lisbon Treaty. The questions raise a wide range of issues relevant to EU criminal law, but also to EU constitutional, administrative and institutional law. A state-centric view of European integration holds that EU criminal law powers were framed to preserve core areas of national sovereignty. Scholarship in the field of EU criminal law is often ambivalent or critical of centralized powers in this field. Addressing the Union s competence creep was at the heart of constitutional reforms incorporated by the Lisbon Treaty. This sentiment explains some unusual features of the field after those revisions: the emergency brake , the special position of the UK, Ireland and Denmark, limits to Court of Justice jurisdiction, the unanimity requirement for states participating in the European Public Prosecutor s office, more sensitive ex ante subsidiarity control, and limiting express criminal law powers to directives. Nevertheless, these limits are constructed from the reference point of EU institutional law. The survey of those elements shows that the foundations of these structures are unreliable. If codification was intended to limit creeping competence , the framers have failed. Case law of the Court of Justice of the European Union after December 2009 suggests that Article 83 TFEU, or even the complete set of legal bases in the Union s area of freedom, security and justice , is not an exhaustive codification of the Union s criminal law powers. The central question in the calculus, the Court s rules on choice of legal bases , has been susceptible to creative drafting and suffers from weak judicial oversight. Legislative practice suggests that the new safeguards can be sidelined in this process. Thus, the central, and important debates in EU criminal law on the meaning of specific concepts like minimum rules , what crimes can be included in the 83(1) list, and how the European Public Prosecutor should operate may be gradually sidelined by the incoming tide , or at least creeping competence in other estuaries. At the same time, Member States cling to pre-Lisbon practices that restrict the exercise of competence but which seem disconnected from the post-Lisbon legal framework. A detailed examination of this field finds anomalies in the external relations law of the Union, where pragmatism prevails. Small elements that have criminal law implications may be included within Union powers where express internal competence is doubtful. In others, declarations of competence appear to reserve powers to the Member States that the Union could lawfully exercise. The Court now accepts ancillary provisions with criminal law relevance in mainstream measures that do not offer the safeguards of the express criminal law provisions. This is demonstrated by analogy with the case law on issues in the area of freedom, security and justice . Thus, social security coordination measures can be based on the free movement provisions, criminal law obligations may be part of the common commercial policy, and agreements on the treatment of suspected pirates may properly be concluded as part of an agreement that is exclusively Common Foreign and Security Policy. The Court even allows the EU legislature to predetermine the success of any legal challenge because it relies primarily on textual evidence in recitals to determine the aim of the legislature. Thus, measures establishing information systems and exchange mechanisms concerning road traffic offences are measures of transport policy, not measures concerning cooperation in criminal matters, and data retention is an internal market measure. These judgments have surprised academics, national governments, and even EU institutions legal services. Questions also arise as to the effectiveness of the new safeguards even when they are not circumvented. The emergency brake may lead to consensualism, but it is not pulled when a Member State position that is presented as a red line is ignored. The pleadings of the opt-out states in key cases suggest that national governments are not policing their opt-out. National parliaments rarely raise formal subsidiarity concerns. Intervention is rare even if an EU proposal raises constitutional issues and overrules significant policy choices in national criminal law. National policy choices may be legitimate even if the Union has the technical capacity to overrule them. National criminal law scholars often argue that integration in criminal law will come at a high personal cost to the victims of that policy unless appropriate safeguards are developed. The Court of Justice has struggled to distinguish between criminal and civil rules in the European Union constitutional system. Instead, it has developed institutional safeguards that require, as far as possible, democratic decision-making. It has also begun to use fundamental rights, and in particular the Charter of Fundamental Rights, to test the legality of Union action. Thus, whilst its standard of review has been criticized in the past, the findings suggest the Court may be better placed to cope with the increasing trend to treat de facto penal law as administrative rules than the corpus of EU judicial review literature suggests. This research has used standard legal research methods but combines these with an element of the law in action in the field of EU transparency law. During the research, it became clear that the key research questions required material that had not been published. In order to study the drafting processes, the study sought and obtained series of documents that were not originally released for public use. These include legislative negotiation documents, legal opinions of the legal services, and even the pleadings of Member States and EU institutions in key constitutional law cases. One document was released through litigation; another is pending litigation. Both cases raise novel points in transparency law that may have wide-reaching consequences on the nature of the EU criminal legislative process. To what extent should it be open to public scrutiny? Should the Union consider strictly defined conferral or procedural limits to the enumerated powers? The history of constitutional limits is that they are circumvented at the first opportunity when a crisis presents itself. It is possible to conceive some which are more difficult to ignore than those which appear to have buckled under the strain of post-Lisbon practice. However, when limits are drafted in a strict form, this can later cause constitutional contortions that call into question the rule of law. Instead, the present criminal competence control has been effectively proceduralized: particular steps must be taken, but their review is likely to be unintrusive or sympathetic. More legal research is required in the pre-legislative stage, even to understand the nature of competence control. Debates in poorly studied legislative forums are likely to shed great light on the Union s constitution: what happens .
  • Nieminen, Tarja (Helsingin yliopisto, 2015)
    Social capital has been widely discussed in research. An increasing amount of literature has linked social capital to various health outcomes and well-being. However, both health and social capital are complex phenomena, and there is still inconsistency in the research findings. The general aim of this study was to examine the associations between social capital, health behaviour and health among adult Finnish population. The conceptualization and operationalization of social capital varies according to discipline and level. In this study, social capital is measured at the individual level assuming that an individual s investment in group activity reflects social capital seen as a resource related to social networks and group membership. Individual benefits are accessed through social connections in varied groups and society. Thus the resources do not reside within the individual but rather in the structure of person s social networks. Social capital was measured on three dimensions in this study: 1) social support, 2) social networks and participation and 3) trust and reciprocity. The association between these dimensions and health were examined. Health was investigated as self-rated health, psychological well-being and mortality. This study utilised the data of the Health 2000 Survey conducted in 2000−2001. Of people aged 30 and over, 89% participated in the home interview and 80% in the general health examination. The study material presents the whole population unusually well. The National Institute for Health and Welfare (THL; formerly the National Public Health Institute, KTL) had the overall responsibility for the project. In addition, the project organization involved a wide range of research and funding agencies. This survey contains a rich armoury of questions about health and illnesses, health behaviour, capacity for work, functional capacity and use of health services. Furthermore, it includes a broad selection of questions used in measuring social capital. The results found an accumulation of social capital and general welfare for the same groups: the highest levels of social capital were found among the young, well-educated and married people. However, all socio-demographic subgroups seem to benefit from social capital. Regardless of all socio-demographic characteristics, high levels of social capital were associated with good health, associations which varied among different health-related behaviours, but social participation had a strong statistical association with all components of health and all health behaviours. Regardless of chronic diseases people with high levels of social capital felt healthier than those with low levels. The positive association between social capital and survival was statistically significant among men and suggestive among women. These findings indicate that social capital contributes to health. Health inequalities between population sub-groups are still substantial. Health could be promoted and health inequalities reduced by developing tools for increasing social participation especially in those groups lacking social capital−and who often also suffer from several health problems.
  • Lehto, Hanna (Helsingin yliopisto, 2015)
    Objective: Aneurysms of the vertebral artery (VA) and its branch posterior inferior cerebellar artery (PICA) are rare, comprising only about 1 to 3% of all intracranial aneurysms. The series published thus far on these lesions are small. We aim to describe the special anatomical and morphological features of these aneurysms compared to aneurysms in other locations, and to describe the variety of symptoms they cause. We describe their treatment and analyze the outcome. Additionally, we describe their anatomy imaged with computed tomography angiography. Patients and methods: We reviewed retrospectively 9 709 consecutive patients with intracranial aneurysms treated in the Department of Neurosurgery at Helsinki University Central Hospital, Finland, between 1934 and 2011. The study population included 268 patients with 284 VA or PICA aneurysms or both. Follow-up data came from the Population Registry Centre (dates of death), Statistics Finland (causes of death), from written questionnaires to patients still alive, medical records of the Department of Neurosurgery, and for those deceased, medical records from all public health services. Results: Among all the aneurysm patients, 5.1% had an aneurysm in the VA or PICA. Most aneurysms, 51%, were located at the VA PICA junction. The proportion of fusiform aneurysms was 28%. Compared to patients with ruptured aneurysms at other locations, patients with a ruptured VA or PICA aneurysm were older and had a higher Fisher grade. Ruptured distal PICA aneurysms also re-bled more regularly. Compared to other ruptured aneurysms, ruptured VA and PICA aneurysms were smaller and more often fusiform. At least one VA or PICA aneurysm was treated in 209 (78%) patients. The most common technique for aneurysm occlusion was clipping, used in 107 aneurysms. Total occlusion of the aneurysm was achieved among saccular aneurysms in 90%, and among fusiform aneurysms in 61%. Within one year of aneurysm diagnosis, 26% of the patients were dead. Among those who survived a minimum one year and in whom the VA or PICA aneurysm received active treatment; those returning to an independent or their previous stage of life amounted to 92%. Conclusion: In treatment of VA and PICA aneurysms, their special anatomical and morphological features are challenge. Despite this, and often severe hemorrhage, most patients surviving the initial stage make a good recovery.
  • Nordman, Nina (Helsingin yliopisto, 2015)
    Analytical microsystems are attractive in modern bioanalysis where sample amounts often are low and fast analyses are required. Microsystems also provide the prospect of integrating several functional elements on a single platform. The aim of this work was to develop analytical microsystems for fast analysis of bio- and drug molecules. For this, microchips with separation- and injection channels and monolithically integrated electrospray ionization (ESI) emitter were fabricated of epoxy photoresist SU-8 by photolithography and adhesive bonding. For peptide mass fingerprinting and protein sequencing characteristic tryptic peptides were fast and easily separated and detected by microchip capillary electrophoresis (MCE)-ESI/mass spectrometry (MS). Additionally, protein identification based on tandem MS fragmentation data of a single tryptic peptide was achieved. Finally, this rapid (total analysis time below ten minutes) microchip method permitted analysis of human muscle cell lysates. For online coupling of microchip capillary isoelectric focusing (cIEF) to ESI/MS a bilateral sheath flow interface or a two-dimensional separation unit was integrated on-chip. Rapid focusing of peptides by their isoelectric points (pI) was achieved without pretreatment of the SU-8 surface. After focusing the peptides were electrokinetically mobilized toward ESI/MS. The two-dimensional chip design enabled unique separation selectivity for peptides based on both pI values and intrinsic electrophoretic mobilities by multiplex-cIEF-transient-isotachophoresis. Rapid metabolic profiling was demonstrated from urine after intake of tramadol or paracetamol. Both phase I- and II metabolites were separated and detected by MCE-ESI/MS within 35 s. In addition, Michaelis-Menten kinetics was successfully determined for the CYP450-mediated oxidation of bufuralol to 1-hydroxybufuralol. Sample preconcentration (pretreatment) was integrated on-chip by solid-phase extraction (SPE) and liquid-phase microextraction (LPME). For SPE, a monolith zone was firmly anchored at the injection cross of the MCE-ESI/MS microchip by laser induced photopolymerization. The monolith was selective toward hydrophobic and hydrophilic sample molecules and enrichment factors as high as 23-fold was achieved with a loading time as short as 25 s. In addition, LPME was easily downscaled to low volume applications and offered selectivity in the analysis of phase I metabolites compared to SPE. In contrast to previous research in the same field this work offers bioanalysis with several on-chip integrated steps (preconcentration, injection, separation, and analysis) without considerably increasing the short analysis times characteristic of microchip assays.